Malignant brain tumors are aggressive, rapidly growing tumors that are refractory to surgery, radiation and chemotherapy and most often kill by uncontrolled local growth in an inelastic confined space. Tumor oncogenesis, metabolic pathways critical for growth and the role of extracellular matrix in infiltration and spread of tumor are poorly understood in malignant brain tumors. New treatment options are needed. In this RFA we will explore central nervous system tumor development and growth patterns, and examine the pentose phosphate pathways to understand malignant cell growth. In glioma tissue cultures, we will further investigate halopyrimidine chemosensitivity and attempt to elucidate its mechanisms and begin clinical trials with halopyrimidines as chemosensitizers with the hope of improving treatment. In Project 1 we will explore the DNA methylation state of glial neoplasms with the hypothesis that hypomethylation is important to their genesis. We will explore methyltransferase gene activity to understand the mechanisms of methylation state change and correlate methylation state with survival. Project 2 will examine the enzymatic systems in glioma cells which provide protection from H2O2 oxidant injury. Pentose phosphate pathway specific enzyme inhibitors will be used to systematically investigate the role of antioxidant systems in vitro and in vivo in glioma tissue and their role in the detoxification of H2O2. Medulloblastoma (Project 3), a pediatric CNS neoplasm, will be examined in 3 cell lines for its interaction with extracellular matrix proteins, its matrix protein receptors and the synthesis of these proteins to understand the tumors propensity to migrate within and outside the CNS. In Project 4, we will quantitate and establish the mechanisms of increased chemosensitivity to BCNU and CisPt in BrdUrd substituted DNA in human glioma cells. We also will evaluate the effect of BrdUrd substitution on the development of BCNU resistance and in BCNU resistant cells. In Project 5, we will begin a phase I dose escalation study of 14 day continuous intra-arterial carotid infusion followed 3 days later by intra-arterial BCNU. When the phase I study is complete, we will begin a phase II study of BrdUrd chemosensitization to determine response rate, duration of response and survival following initiation of this therapy. In summary, we hope to improve brain tumor therapy by increasing understanding of development, spread, growth and control of proliferation of primary central nervous system tumors.
